Body Composition Parameters, Adiponectin, Leptin and Adiponectin/Leptin Ratio are Correlated with LH/FSH Ratio in Women with PCOS but not in Women without PCOS

Objective: To investigate the correlation between body composition parameters, adiponectin, leptin and the adiponectin/leptin ratio and the LH/FSH ratio in women with polycystic ovary syndrome (PCOS). Methods: A cross-sectional study was conducted at Reproductive Cluster Yasmin, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, with sixty women with PCOS and sixty healthy women as controls (matched for age and BMI). Body composition parameters, including body weight, body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), percent body fat (PBF), visceral fat area (VFA), percent subcutaneous fat (PSF) and skeletal muscle mass (SMM), were measured; levels of fasting glucose, fasting insulin, testosterone, and sex hormone binding globulin (SHBG) were measured; and homeostatic model assessment for insulin resistance (HOMA-IR) values, anti-Mullerian hormone (AMH), free androgen index (FAI), Ferriman-Gallwey (FG) score, adiponectin levels, leptin levels, adiponectin/leptin ratio, LH, FSH and LH/FSH ratio were measured. Results: Body composition parameters (body weight, BMI, WC, WHR, PBF, VFA, PSF, SMM) were not significantly different between women with PCOS and controls. Fasting insulin (P<0.05), HOMA-IR (P<0.05), AMH (P<0.01), FAI (P<0.01), FG score (P<0.01) and LH/FSH ratio (P<0.05) were higher in PCOS women. Adiponectin (P<0.01) was lower in PCOS women, while leptin and the adiponectin/leptin ratio were not significantly different between groups. Most of body composition parameters, adiponectin, leptin and adiponectin/leptin ratio were correlated with HOMA-IR in both groups. SMM was positively correlated with the LH/FSH ratio, while body weight, BMI, WC, PBF, VFA, and PSF were inversely correlated with the LH/FSH ratio in PCOS patients but not in controls. WHR was not correlated in either group. Leptin (r=-0.278; P<0.05) was negatively correlated with the LH/FSH ratio only in the PCOS group. Adiponectin (r=0.394; P<0.01) and the adiponectin/leptin ratio (r=0.413; P<0.01) were also positively correlated with the LH/FSH ratio only in the PCOS group. AMH was correlated with the LH/FSH ratio, whereas testosterone level, FAI, FG score, fasting insulin level and HOMA-IR value were not correlated with the LH/FSH ratio in PCOS women. Conclusion: Most of the body composition parameters, leptin, adiponectin and the adiponectin/leptin ratio were significantly correlated with HOMA-IR in both groups. However, correlations of those parameters with LH/FSH ratio were found only in PCOS but not in women without PCOS. Adiponectin and leptin may play a significant role in the mechanism of neuroendocrine disorders in PCOS, which is characterized by an increased LH/FSH ratio. Keywords: adiponectin, adiponectin/leptin ratio, body composition, HOMA-IR, leptin, LH/FSH ratio, PCO

Ekspresi Protein Foxo1 dan Gen Glukosa 6 Fosfatase pada Tikus dengan Diet Restriksi Vitamin B12

Pada penelitian awal didapatkan diet restriksi vitamin B12 menyebabkan hiperhomosisteinemia dan resistensi insulin, yang ditandai oleh hiperglikemia dan meningkatnya nilai Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Dengan menggunakan sampel jaringan biologik tersimpan, hati tikus Spraque-Dawley dari penelitian tersebut, penelitian lanjutan ini bertujuan mengetahui penyebab hiperglikemia, dalam hubungannya dengan proses glukoneogenesis, dengan melihat ekspresi forkhead box protein-O1 (FoxO1) dan gen glukosa 6 fosfatase (G6Pc). Adapun sampel terdiri dari 4 kelompok: kelompok kontrol dan tiga kelompok dengan diet restriksi vitamin B12 masing-masing selama 4, 8, dan 12 minggu. Ekspresi FoxO1 diperiksa dengan metode kuantitatif Western-Blot, sedangkan gen G6Pc diperiksa dengan metode real-time Polymerase Chain Reaction (rt-PCR). Hasil yang diperoleh, tidak terdapat perbedaan bermakna ekspresi FoxO1 (P > 0,05) dan gen G6Pc (P > 0,05) antara kelompok tikus kontrol dan kelompok diet restriksi vitamin B12. Hal ini menunjukkan, hiperglikemia pada diet restriksi vitamin B12 tidak terkait dengan glukoneogenesis. Pada kondisi resistensi insulin, insulin masih dapat meneruskan efek metaboliknya melalui jalur lain, seperti melalui reseptor yang memiliki kemiripan struktur dan fungsi dengan reseptor insu   lin. Penyebab-penyebab lain terjadinya hiperglikemia seperti gangguan utilisasi glukosa oleh sel dan gangguan proses glikogenesis perlu diteliti lebih lanjut.Pada penelitian awal didapatkan diet restriksi vitamin B12 menyebabkan hiperhomosisteinemia dan resistensi insulin, yang ditandai oleh hiperglikemia dan meningkatnya nilai Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Dengan menggunakan sampel jaringan biologik tersimpan, hati tikus Spraque-Dawley dari penelitian tersebut, penelitian lanjutan ini bertujuan mengetahui penyebab hiperglikemia, dalam hubungannya dengan proses glukoneogenesis, dengan melihat ekspresi forkhead box protein-O1 (FoxO1) dan gen glukosa 6 fosfatase (G6Pc). Adapun sampel terdiri dari 4 kelompok: kelompok kontrol dan tiga kelompok dengan diet restriksi vitamin B12 masing-masing selama 4, 8, dan 12 minggu. Ekspresi FoxO1 diperiksa dengan metode kuantitatif Western-Blot, sedangkan gen G6Pc diperiksa dengan metode real-time Polymerase Chain Reaction (rt-PCR). Hasil yang diperoleh, tidak terdapat perbedaan bermakna ekspresi FoxO1 (P > 0,05) dan gen G6Pc (P > 0,05) antara kelompok tikus kontrol dan kelompok diet restriksi vitamin B12. Hal ini menunjukkan, hiperglikemia pada diet restriksi vitamin B12 tidak terkait dengan glukoneogenesis. Pada kondisi resistensi insulin, insulin masih dapat meneruskan efek metaboliknya melalui jalur lain, seperti melalui reseptor yang memiliki kemiripan struktur dan fungsi dengan reseptor insulin. Penyebab-penyebab lain terjadinya hiperglikemia seperti gangguan utilisasi glukosa oleh sel dan gangguan proses glikogenesis perlu diteliti lebih lanjut

EFFECT OF AEROBIC EXERCISE ON SHORT-AND LONG-TERM MEMORY IN ADULT MALE WISTAR RATS

Objective: Memory is an essential function of cognition in humans, but an age- and disease-related deterioration of this function is common. The currently known treatments have high failure rates, and thus, the slowing down of memory degeneration at an early age is the preferred preventive approach. Exercise, specifically aerobic exercise, has been proven to enhance memory via various pathways, such as neurogenesis, angiogenesis, and growth factor expression. The aim of this study is to assess the effect of aerobic exercise on short-term and long-term memory function in rats. Methods: Twenty-four male Wistar rats aged 7 mo were randomly distributed into four groups: Control, short-term memory (C-S); Control, long-term memory (C-L); Aerobic, short-term memory (A-S); and Aerobic, long-term memory (A-L). The aerobic groups received exercise treatment for 30 min each five times per week, at a treadmill speed of 20 m/min. The treatment duration was 8 w. Short-term memory was assessed using the forced alteration Y-maze test, and long-term memory was assessed using the object location task. Results: The findings showed that rats placed under the aerobic exercise regimen had significantly better long-term memory function at the end of 8 w (p = 0.006), while no significant difference was observed in short-term memory function between the aerobic exercise group and the control group. Conclusion: The present study shows that aerobic exercise is beneficial in improving long-term memory function in rats

Combination of Aerobic Exercise and Continuous Environmental Enrichment Improves Adult Male Rats’ Spatial Memory: Study on Hippocampal Insulin Like Growth Factor 1 (IGF-1) and Fibroblast Growth Factor 2 (FGF-2) Expression

BACKGROUND: Memory declines with the progression of age through the neurodegeneration process. Aerobic exercise and environmental enrichment can delay neurodegeneration by improving neuroplasticity via expression of insulin like growth factor 1 (IGF-1), fibroblast growth factor 2 (FGF-2) and other proteins. Combination treatment of aerobic exercise and continuous environmental enrichment and their effect on the expression of IGF-1 and FGF-2 which were expected to improve memory function has not been studied previously. Thus, this study aimed to observe it.METHODS: This is an experimental research using 24 male Wistar rats (Rattus norvegicus, 300-400 g, age 7-8 months) divided randomly into 4 groups: control (C), aerobic exercise (A), continuous (EE), and combination of aerobic exercise and continuous environmental enrichment (A-EE). At the end of an 8-week treatment, rats were sacrificed, and an enzyme-linked immunosorbent assay (ELISA) examination was performed to assess hippocampal IGF-1 and FGF-2 levels.RESULTS: In the 8th week, A-EE group showed the best improvement in rats’ spatial memory (47.84±10.6 %) followed by EE group (45.03±4.1 %), A group (38.61±3.8 %), and C group (22.76±7.12 %). However, A-EE group’s hippocampal IGF-1 (16.21±7.56 ng/mg protein) and FGF-2 (1.29±0.57 ng/mg protein) expression were not higher than other groups.CONCLUSION: Improvement in memory function in the combination group is a result of induction of various growth factors’ expression in the hippocampus, including IGF-1 and FGF-2, but the primary pathway of memory function improvement may be from other growth factors.KEYWORDS: spatial memory, aerobic exercise, environmental enrichment, hippocampus, IGF-1, FGF-

EFFECT OF HIBISCUS SABDARIFFA LINN METHANOLIC EXTRACT ON HEART HYPERTROPHY INDEX AND PGC-1α IN OVERTRAINED RAT

Objective: Studies have shown that prolonged physical exercise increases ventricular wall mass. Physiologically, this increase is followed by an increase of mitochondrial biogenesis. However, increases of ventricular mass in some cardiovascular diseases are not followed by an increase of PPARγ coactivator-1α (PGC-1α), a marker of mitochondrial biogenesis. No data regarding cardiac PGC-1α during an excessive physical exercise program that causes pathological conditions (overtraining) are available. Thus, we aimed to determine the effect of overtraining on cardiac hypertrophy index and PGC-1α level. Furthermore, we aimed to elucidate the cardio protective effect of Hibiscus sabdariffa Linn. (HSL) administration on these cardiac parameters. Methods: Twenty-five male adult Wistar rats aged 8–10 w were randomly divided into five groups: control (C), control-HSL (C-HSL), aerobic training (A), overtraining (OT), and overtraining-HSL (OT-HSL). Treatments were conducted five times a week, for 11 w. Differences in heart mass were determined by measuring ratios of ventricular weight to body weight (hypertrophy index). PGC-1α levels were measured using an ELISA method. Results: We found that overtraining increased ventricular wall mass; however, it did not increase cardiac PGC-1α levels, whereas mild-aerobic exercise robustly increased cardiac levels of PGC-1α. Furthermore, administration of a methanol extract of HSL did not show any significant effect on cardiac mass or PGC-1α level. Conclusion: Thus, our study showed that ventricular hypertrophy elicited by overtraining conditions was not followed by an increase in cardiac PGC-1α, and administration of H. sabdariffa extract did not ameliorate this condition

EFFECT OF HIBISCUS SABDARIFFA LINN ON IL-6 AND TNF- α LEVELS IN OVERTRAINED RAT HEART

Objective: This study aims to determine the effect of Hibiscus sabdariffa Linn. (HSL) administration on the interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels in rat heart. Overtraining was proven to increase the IL-6 and TNF-α levels in the blood, and HSL had anti-inflammatory and anti-oxidant properties. However, no studies have been conducted on the effect of methanolic extract of HSL administration on the IL-6 and TNF-α levels in overtrained rat heart. Methods: This study used 25 male adult Wistar rats aged 8–10 w and weighing 200–250 g. The rats were randomly divided into five groups: control (C), control H. sabdariffa Linn (C+HSL), overtraining (OT), overtraining H. sabdariffa Linn (OT+HSL), and aerobic (A). Treatment was given 5 times a week for 11 w. At the end of the study, the IL-6 and TNF-α levels were measured using a standard ELISA kit. Results: IL-6 and TNF-α levels in the heart were the highest in the overtraining group. The group that received HSL administration showed the lowest TNF-α and IL-6 levels. Conclusion: HSL could be a used to protect the heart from an inflammatory state, particularly in an overtraining condition

Adult neurogenesis and mitochondria play a role in hippocampal plasticity in mouse models of neurodegenerative diseases

La neurogenèse adulte est cruciale pour certaines fonctions mnésiques dépendantes de l'hippocampe. La mise en évidence d'une altération de la neurogenèse dans le cerveau de souris transgéniques modèles de la maladie d'Alzheimer (MA), en parallèle d'une réduction du contenu mitochondrial de leurs nouveaux neurones ouvre une nouvelle piste de recherche ciblant les mitochondries. Aujourd'hui, l'hypothèse d'un rôle causal des dysfonctionnements mitochondriaux dans l'étiologie des pathologies neurodégénératives est particulièrement pertinente dans la MA. Les mitochondries, " centrales électriques " et régulateurs du métabolisme oxydatif, forment un réseau dynamique qui s'adapte aux différents types et contextes cellulaires, via des événements antagonistes de fusion et de fission de leurs membranes. Les protéines clés ont été identifiées, dont OPA1 qui permet la fusion. Les dysfonctionnements de cette dynamique influent non seulement sur la forme et la distribution des mitochondries dans les neurones, mais affectent aussi leurs principales activités que sont respiration, régulation calcique, production de ROS et apoptose. Dans les neurones, cellules excitables à l'architecture complexe, les dysfonctionnements mitochondriaux ont des conséquences particulièrement cruciales pour la transmission synaptique. Au cours de cette thèse, nous avons étudié parallèlement des souris modèles de la MA, les souris Tg2576 (mutation d'APP) et des souris OPA1+/-, porteuses d'une mutation d'OPA1, modèles de l'Atrophie Optique Dominante. Nous avons observé chez ces deux lignées de souris une altération précoce des performances dans des tests comportementaux mettant en jeu le gyrus denté et les nouveaux neurones (tests de localisation d'objet et de séparation de patron). Nous avons démontré chez les souris Tg2576 et OPA1+/- que ces déficits cognitifs sont associés à des perturbations de la neurogenèse hippocampique adulte. De plus, les nouveaux neurones de l'hippocampe présentent une densité d'épines dendritiques réduite, ainsi qu'un déficit marqué de leur contenu mitochondrial. Par ailleurs, nous montrons que la surexpression du facteur de transcription proneural Neurod1 dans les progéniteurs hippocampiques favorise leur intégration et rétablit la biomasse mitochondriale des nouveaux neurones, chez les souris Tg2576. D'autre part, une restauration des performances mnésiques peut de façon remarquable être obtenue en soumettant les souris OPA1+/- à un exercice physique volontaire, qui favorise la biogenèse mitochondriale. Ainsi, nos travaux mettent en évidence un rôle central, encore inexploré, de la dynamique mitochondriale dans les processus cognitifs liés à la neurogenèse adulte dans l'hippocampe et ouvrent la voie à de nouvelles pistes thérapeutiques.Adult neurogenesis is crucial for some hippocampus-dependent memory functions. Both the demonstration of an alteration of neurogenesis in the brain of transgenic mouse models of Alzheimer's disease (AD), in parallel with a reduction in the mitochondrial content of their new neurons, open a new research avenue targeting the mitochondria. Today, the hypothesis of a causal role of mitochondrial dysfunctions in the etiology of neurodegenerative pathologies is particularly relevant in AD. Mitochondria, "power plants" and regulators of oxidative metabolism, form a dynamic network that adapts to different cell types and contexts, via antagonistic events of fusion and fission of their membranes. Key proteins have been identified, including OPA1 that allows fusion. Dysfunctions of this dynamics affect not only the shape and distribution of mitochondria in neurons, but also alter their main activities: respiration, calcium regulation, ROS production and apoptosis. In neurons, excitable cells with complex architecture, mitochondrial dysfunctions have particularly crucial consequences for synaptic transmission. In this thesis, we studied in parallel an AD mouse model, the Tg2576 mice (APP mutation) and the OPA1 +/- mice, carrying a mutation of OPA1, a Dominant Optic Atrophy model. In both mouse lines, we observed precocious performance alterations in behavioral tests involving the dentate gyrus and new neurons (object location, pattern separation tests). We demonstrated in Tg2576 and OPA1 +/- mice that these cognitive deficits are associated with disturbances of adult hippocampal neurogenesis. In addition, the new granular neurons have a reduced density of dendritic spines, as well as a marked deficit of their mitochondrial content. In addition, overexpression of the proneural transcription factor Neurod1 in hippocampal progenitors favors their synaptic integration and restores the mitochondrial biomass of new neurons in Tg2576 mice. On the other hand, a restoration of memory performance can be remarkably achieved by subjecting the OPA1 +/- mice to voluntary physical exercise, which has a promoting effect on mitochondrial biogenesis. Thus, our work reveals a central role, still unexplored, of the mitochondrial dynamics in the cognitive processes related to adult hippocampal neurogenesis and opens the way to new therapeutic promises

Prevention of insulin resistance with <em>Hibiscus sabdariffa</em> Linn. extract in high-fructose fed rat

Background: Dyslipidemia and stress oxidative play an important role as the cause of insulin resistance. One herb that has potent antioxidant effect and may improve dyslipidemia is Hibiscus sabdariffa Linn. The aim of this study was to evaluate the effect of Hibiscus sabdariffa Linn. extract on fasting blood glucose level, fasting blood insulin level, and insulin resistance index (HOMA-IR) in high-fructose fed rat.Methods: This was an experimental study in 25 Sprague-Dawley rats which were administered with a high-fructose diet (10% ad libitum) and Hibiscus sabdariffa Linn. extract at a dose of 100, 200, and 400 mg/kgBW/d simultaneously for 5 weeks. At the end of study, fasting blood glucose level, fasting blood insulin level and insulin resistance index (HOMA-IR) were measured.Results: Fasting blood glucose, blood insulin, and HOMA-IR level of rats given high-fructose diet with Hibiscus sabdariffa Linn. at dose 100 mg/kgBW/d were not significantly different than the group of rats given only high-fructose fed. While at the dose of 400 mg/kgBW/d, they were significantly lower than the group given only high-fructose fed (4.84 mmol/L vs 6.11 mmol/L, 0.07 µU/L vs 0.3 µU/L, and 0.02 vs 0.08 respectively).Conclusion: Oral administration of Hibiscus sabdariffa Linn. could prevent the development of insulin resistance induced by high-fructose diet in the rat. </p

Les mitochondries impliquées dans la neurogenèse adulte jouent un rôle dans la plasticité de l’hippocampe dans des modèles murins de maladies neurodégénératives

La neurogenèse adulte est cruciale pour certaines fonctions mnésiques dépendantes de l'hippocampe. La mise en évidence d'une altération de la neurogenèse dans le cerveau de souris transgéniques modèles de la maladie d'Alzheimer (MA), en parallèle d'une réduction du contenu mitochondrial de leurs nouveaux neurones ouvre une nouvelle piste de recherche ciblant les mitochondries. Aujourd'hui, l'hypothèse d'un rôle causal des dysfonctionnements mitochondriaux dans l'étiologie des pathologies neurodégénératives est particulièrement pertinente dans la MA. Les mitochondries, " centrales électriques " et régulateurs du métabolisme oxydatif, forment un réseau dynamique qui s'adapte aux différents types et contextes cellulaires, via des événements antagonistes de fusion et de fission de leurs membranes. Les protéines clés ont été identifiées, dont OPA1 qui permet la fusion. Les dysfonctionnements de cette dynamique influent non seulement sur la forme et la distribution des mitochondries dans les neurones, mais affectent aussi leurs principales activités que sont respiration, régulation calcique, production de ROS et apoptose. Dans les neurones, cellules excitables à l'architecture complexe, les dysfonctionnements mitochondriaux ont des conséquences particulièrement cruciales pour la transmission synaptique. Au cours de cette thèse, nous avons étudié parallèlement des souris modèles de la MA, les souris Tg2576 (mutation d'APP) et des souris OPA1+/-, porteuses d'une mutation d'OPA1, modèles de l'Atrophie Optique Dominante. Nous avons observé chez ces deux lignées de souris une altération précoce des performances dans des tests comportementaux mettant en jeu le gyrus denté et les nouveaux neurones (tests de localisation d'objet et de séparation de patron). Nous avons démontré chez les souris Tg2576 et OPA1+/- que ces déficits cognitifs sont associés à des perturbations de la neurogenèse hippocampique adulte.[...]Adult neurogenesis is crucial for some hippocampus-dependent memory functions. Both the demonstration of an alteration of neurogenesis in the brain of transgenic mouse models of Alzheimer's disease (AD), in parallel with a reduction in the mitochondrial content of their new neurons, open a new research avenue targeting the mitochondria. Today, the hypothesis of a causal role of mitochondrial dysfunctions in the etiology of neurodegenerative pathologies is particularly relevant in AD. Mitochondria, "power plants" and regulators of oxidative metabolism, form a dynamic network that adapts to different cell types and contexts, via antagonistic events of fusion and fission of their membranes. Key proteins have been identified, including OPA1 that allows fusion. Dysfunctions of this dynamics affect not only the shape and distribution of mitochondria in neurons, but also alter their main activities: respiration, calcium regulation, ROS production and apoptosis. In neurons, excitable cells with complex architecture, mitochondrial dysfunctions have particularly crucial consequences for synaptic transmission. In this thesis, we studied in parallel an AD mouse model, the Tg2576 mice (APP mutation) and the OPA1 +/- mice, carrying a mutation of OPA1, a Dominant Optic Atrophy model. In both mouse lines, we observed precocious performance alterations in behavioral tests involving the dentate gyrus and new neurons (object location, pattern separation tests). We demonstrated in Tg2576 and OPA1 +/- mice that these cognitive deficits are associated with disturbances of adult hippocampal neurogenesis. [...

Memory formation orchestrates the wiring of adult-born hippocampal neurons into brain circuits

During memory formation, structural rearrangements of dendritic spines provide a mean to durably modulate synaptic connectivity within neuronal networks. New neurons generated throughout the adult life in the dentate gyrus of the hippocampus contribute to learning and memory. As these neurons become incorporated into the network, they generate huge numbers of new connections that modify hippocampal circuitry and functioning. However, it is yet unclear as to how the dynamic process of memory formation influences their synaptic integration into neuronal circuits. New memories are established according to a multistep process during which new information is first acquired and then consolidated to form a stable memory trace. Upon recall, memory is transiently destabilized and vulnerable to modification. Using contextual fear conditioning, we found that learning was associated with an acceleration of dendritic spines formation of adult-born neurons, and that spine connectivity becomes strengthened after memory consolidation. Moreover, we observed that afferent connectivity onto adult-born neurons is enhanced after memory retrieval, while extinction training induces a change of spine shapes. Together, these findings reveal that the neuronal activity supporting memory processes strongly influences the structural dendritic integration of adult-born neurons into pre-existing neuronal circuits. Such change of afferent connectivity is likely to impact the overall wiring of hippocampal network, and consequently, to regulate hippocampal function